© Springer Science+Business Media New York 2014
Gary R. Lichtenstein (ed.)Medical Therapy of Ulcerative Colitis10.1007/978-1-4939-1677-1_2323. Treatment of Severe Ulcerative Colitis
(1)
Department of Medicine, Daisy Hill Hospital, 5 Hospital Road, Newry, Co., Down, N. Ireland, UK
(2)
The Henry D. Janowitz Division of Gastroenterology, The Icahn School of Medicine at Mount Sinai, 1751 York Ave., New York, 10128, NY, USA
Keywords
SevereUlcerative colitisTreatmentAssessment scoreInvestigationMonitoringCorticosteroidsCyclosporine6-Mercaptopurine/azathioprineInfliximab antibioticsParenteral nutritionSurgeryFulminant colitisToxic megacolonDefinitions and Assessing Severity
Severe ulcerative colitis (UC) was first defined by Truelove and Witts in 1955 using six simple criteria without any requirement for a sigmoidoscopic examination—six or more stools per day with one of the following: large amounts of blood, fever >37.8 °C, tachycardia >90, ESR > 30 mm/h, and hemoglobin <10.5 g/dl. These criteria are easily measured and have stood the test of time over half a century [1]. The Mayo Clinic Index (with slight variations also known as the Sutherland Index or the UC Disease Activity Index) has become a frequently used scoring index in clinical trials and includes sigmoidoscopic appearance and the physician’s global assessment. Another score known as the Modified Truelove-Witts Scoring Index, or the Lichtiger score, has been used most frequently in patients with intravenous (IV) corticosteroid-refractory UC. The Lichtiger score includes assessments for nocturnal bowel movements, incontinence, abdominal pain, cramping and tenderness, and the overall sense of “well-being.” While all of these scores list the salient features defining disease activity, the term “severe ulcerative colitis” as used in this chapter will refer to those patients with ongoing frequent bloody diarrhea with systemic signs and/or symptoms that significantly limit the patient’s quality of life and who fail to improve with maximal outpatient therapies and require hospitalization for further management.
Toxic megacolon refers to patients with dilation of the colon of >6 cm diameter associated with severe systemic toxicity. It is important to recognize that patients may present with toxicity without colonic dilation and are still at graver risk than patients with severe colitis without toxicity. Fulminant colitis is defined as any colitis that, in addition to the features of severe colitis, becomes rapidly worse, usually manifesting as severe abdominal pain and continuous bleeding requiring multiple transfusions. Medical therapy is inappropriate in fulminant colitis, and colectomy is the only suitable treatment.
Management: Investigations and Monitoring
The immediate goals of therapy are to reduce the signs and symptoms of the severe acute attack, allow the taper of corticosteroids, and initiate a strategy to achieve a long-term corticosteroid-free remission. The primary goal is not the avoidance of surgery. This is important to emphasize that the mortality from severe UC reduced dramatically from 24 to 7 % with the introduction of IV corticosteroids in the 1960s. Now the mortality in most units should be <1 %, and this reduction over the last 50 years is almost exclusively due to timely and expert surgical input. Close collaboration with a surgeon is therefore essential.
A sigmoidoscopy is done to assess disease severity and obtain biopsies to exclude a superimposed etiology, e.g., infection with Clostridium difficile (C. difficile) and cytomegalovirus (CMV). A full colonoscopy incurs the risk of perforation in these patients, so an unprepped sigmoidoscopy with minimal air insufflation is sufficient and yields the information required at that moment in time to correctly manage the patient.
The incidence of C. difficile in hospitalized patients with UC is rising dramatically and results in increased length of stay and morbidity and mortality [2]. The diagnosis is challenging because patients with severe UC may not have the usual risk factors of antibiotic exposure or recent hospitalization, pseudomembranes are generally not seen at sigmoidoscopy, and if stool toxin assays are relied upon, multiple stool specimens may be necessary before the infection is confirmed. The use of a polymerase chain reaction test for C. difficile significantly reduces false-negative results [3].
CMV superinfection may occur in severe colitis and should be considered in the patient who is not responding to maximal immunosuppressive therapy. The diagnosis can be confirmed with sigmoidoscopic biopsy and viral culture; treatment with ganciclovir may lead to clinical improvement. Evidence of CMV disease can be found in 30 % of cases of severe colitis and its exact role continues to be debated [4]. However, in the patient with fulminant colitis with continuing deterioration, colectomy should not be deferred while awaiting a possible response to treatment for CMV infection.
A plain abdominal film should be performed on admission. Not only will this detect a megacolon but also more subtle radiographic findings of increased small intestinal gas, which predicts a greater likelihood of failure of medical therapy [5]. Any complaints of increasing abdominal pain or distention, especially in a febrile patient, should prompt a CT scan of the abdomen and pelvis to detect subtle signs of colonic perforation, which may be first seen as air within the wall of the colon. The presence of these findings should be followed by emergent subtotal colectomy. In general, medications with anticholinergic or narcotic properties should be avoided because of the theoretical risk of reducing bowel tone and worsening colonic dilatation.
Corticosteroids
IV corticosteroids have been the mainstay of treatment for acute severe colitis for over 50 years [1]. Patients are treated with IV hydrocortisone 100 mg three times daily or an equivalent dose of an alternative IV corticosteroid. There is no benefit to treatment with a higher daily dose of corticosteroids, which exposes the patient to a higher risk of side effects without increased rate of success. There is no benefit to continuous IV corticosteroid infusion compared to bolus dosing three times daily. Historically, almost half of patients with severe colitis did not respond to high-dose IV corticosteroids and required colectomy [6]. The colectomy rate for severe UC has remained consistent over the last 40 years [7].
More recently, it has been recognized that by day 3 of IV corticosteroids, there is a high rate of colectomy in those patients with continued bleeding and greater than six bowel movements daily, elevated CRP, or fevers [8, 9]. These patients, as well as patients who are not decisively improved by days 5–7, should be offered IV cyclosporine, infliximab, or surgery.
Cyclosporine
IV cyclosporine is effective therapy in severe colitis. Multiple series have replicated the 80 % immediate response rate in hospitalized patients failing IV corticosteroids first demonstrated by Lichtiger et al. [10]. Van Assche and colleagues found no difference in efficacy when they compared IV cyclosporine 2–4 mg/kg [11]. It is thought that cyclosporine levels of approximately 200–400 μg/ml are therapeutic during the IV phase. The median time to response is 4 days [12], and predictive factors for failure to respond to cyclosporine include persistent fevers, tachycardia, elevated CRP, hypoalbuminemia, and deep colonic ulcerations [13].
Cyclosporine should only be used by clinicians experienced with its use and who have access to drug level monitoring. Contraindications to its use include active infection, uncontrolled hypertension, renal impairment, and unreliable patients since frequent physician visits are required following discharge from hospital. More common but less severe side effects include paresthesias, hypertension, hypertrichosis, headache, abnormal liver function tests, hyperkalemia, and gingival hyperplasia [14]. Renal function must be monitored closely and serum cholesterol and magnesium should be checked. Low levels of either increase the risk of neurotoxicity, including seizures. Patients with low levels of cholesterol (cholesterol < 120 mg/dl or 3 mmol/l) should be started on lower doses of cyclosporine (or avoid cyclosporine and use infliximab instead, see below), and cholesterol and cyclosporine levels should be monitored daily.
During intervals of triple immunosuppression with corticosteroids, cyclosporine, and thiopurine, we give patients prophylaxis against Pneumocystis jiroveci (carinii) with trimethoprim/sulfamethoxazole 960 mg daily. Serious infections during the IV cyclosporine phase may be due to the concomitant use of corticosteroids rather than the serum level of cyclosporine.
For transitioning to oral cyclosporine before hospital discharge, the IV dose the patient was receiving at the end of the IV phase is doubled and is given in two divided doses daily and generally aiming for trough oral cyclosporine levels of 100–250 μg/ml. In addition, treatment with a thiopurine (6-mercaptopurine or azathioprine) is continued or initiated, and the patient is started on a weekly corticosteroid taper. Failure to taper the prednisone and cyclosporine by 3–6 months is considered a failure. Patients who have already been treated unsuccessfully with an adequate course of a thiopurine prior to cyclosporine are less likely to maintain a long-term remission after the discontinuation of cyclosporine.
6-Mercaptopurine/Azathioprine
Multiple open-label series have demonstrated long-term success with initiating thiopurine therapy during the oral cyclosporine phase in those patients not previously exposed to thiopurines. However, the long-term success rate is lower in those patients who have previously failed adequate courses of thiopurine therapy [15, 16]. In the largest series to date, 83 % of 142 patients had an initial response to cyclosporine and avoided colectomy during hospitalization [16]. Of the 118 patients who responded, 41 (35 %) required a future colectomy. The rate of colectomy in those already taking azathioprine compared with those not previously exposed to azathioprine was 59 % vs. 31 %, respectively. Life-table analysis demonstrated that although only 33 % of patients required colectomy at 1 year, 88 % required colectomy at 7 years.
For patients who have a complete remission in response to cyclosporine and then have a relapse months or years later, a second course of IV cyclosporine followed by oral cyclosporine may be a successful strategy. In 32 patients who flared a mean of 24 months after their initial cyclosporine-induced remission, 44 % avoided colectomy at 3 years after the second course of cyclosporine [17]. Predictors of higher rate of colectomy in these patients were hypoalbuminemia and the presence of C. difficile.